The present invention pertains to processes for the resolution of optical isomers of lithium pantoate without the use of optically active resolving agents.
Pantolactone is used for the production of pantothenyl alcohol, pantothenic acid and its salts, such as, for example, calcium pantothenate, which possess vitamin activity and are useful as vitamins. Since such biological activity as vitamins is exhibited only by D(+) isomers, a method is required for resolving racemic mixtures of pantolactone. The resolution can be effected either with pantolactone itself or with calcium pantothenate.
Of the many conventional methods for the resolution of optical isomers, such as adsorption, distillation, use of resolving agents, enzymatic or microbiological separation, conversion to diastereoisomeric pairs of salts, selective or preferential crystallization, and electrostatic separation, the only methods that have been found heretofore to be suitable for the resolution of optical isomers of pantolactone were the use of diastereoisomeric pairs of salts or preferential crystallization of ammonium pantoate which latter method is described, for example, in U.S. Pat. No. 3,529,022. Optical isomers of calcium pantothenate can also be resolved by preferential crystallization.
For separation by formation of pairs of diastereoisomeric salts, the process consists generally either in conversion of the racemic mixture of pantolactones with a suitable optically active base, or conversion of a metal salt of the racemic mixture of pantolactone with a salt of an optically active base and a strong acid. This conversion is effected generally in an alcoholic, aqueous alcoholic, or aqueous medium. There is thus obtained a salt of an optically active isomer having a degree of purity that is dependent upon the solvent and the base used. The corresponding enantiomorphs remain in the mother liquor. The salt and the mother liquor are then separated and the salt is treated in such manner that, after addition of acid, the desired optical isomer of pantolactone is isolated and the base is recovered. The unwanted optically inactive isomer of pantolactone is racemized and the racemic mixture is again resolved to obtain the desired optical isomer.
Optically active bases that were used heretofore included naturally occurring alkaloids such as quinine and ephedrine as well as synthetic optically active compounds such as L-threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol. Of the synthetic optically active compounds, .beta.-phenylethylamine and dehydroabietylamine are also of importance.
Another method of resolving DL-pantolactones which is described in U.S. Pat. No. 2,383,524 depends upon the use of anhydrides of diacyl-D-tartaric acids, with which the pantolactone is esterified. Pyridine salts of the racemic esters are then formed and, because of their differences in solubility in benzene, the optical isomers are then separated from each other.
For separating racemic pantolactone into its optical isomers by means of preferential crystallization, the racemic mixture is converted into the corresponding ammonium salt and the differences in solubilities of the D and L-ammonium pantoates with respect to the DL-ammonium pantoate racemic mixture in various solvents is utilized for separating the two isomers. The thus-obtained D and L-ammonium pantoate are separated and are so treated that, following the addition of acid, the desired optically active pantolactone is isolated in conventional manner. DL-calcium pantothenate is also susceptible to resolution by preferential crystallization in a manner similar to that used for separating racemic ammonium pantoate.
The foregoing methods have a number of disadvantages. The usefulness of the method for separating optical isomers by means of pairs of diastereoisomeric salts is limited by the bases that are required which are mostly naturally occurring alkaloids. Furthermore, because the cost of such bases is very high, it is necessary to recover the bases, which adds to the costs. Since these bases are also toxic or most highly active physiologically, this constitutes a further concomitant disadvantage. By racemization of the unwanted isomers the salt with the optically active base that is used must be cleaved into its separate components, otherwise the optically active base would also be racemized. This cleavage, combined with the further treatments that are required, represent a considerable additional expense.
By using L-threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol, which is an intermediate in the production of chloramphenicol, one is necessarily dependent upon the extent of the use of that compound in the production of chloramphenicol. The same reservations that apply to naturally occurring alkaloids also apply in the case of this resolving agent.
In the case of dehydroabietylamine the required higher dilution of the mixture that is to be resolved is a disadvantage because of the increased expenses that are incurred.
The use of diacyl-D-tartaric acid anhydrides is limited likewise by high cost and the treatments that are required as well as by the toxic solvents that are required.
Although a number of the disadvantages of processes of using optically active bases such as, for example, the difficulty of procuring the bases, their high cost, and the high cost for subsequently recovering the bases are avoided in the process of separating the optical isomers of pantolactone by preferential crystallization of ammonium pantoate because ammonia is readily available, the process is nonetheless fraught with a number of disadvantages. When pantolactone is reacted with ammonia, for example, the amide of pantoic acid is also obtained as well as the desired ammonium pantoate together with a series of further reaction products, such as amines and amides which to a great extent unfavorably affect the subsequent selective crystallization which is a very delicate procedure that is readily disturbed by even a small proportions of such by-products. Even with great care, the production of these by-products cannot be entirely avoided. A further disadvantage of the use of ammonium pantoate for separating the optical isomers of pantolactone from each other is that the unwanted isomer cannot readily be racemized. Ammonium pantoate cannot itself directly racemize since it is converted to various of the same by-products that form when pantolactone is reacted with ammonia. For the purpose of racemization, the unwanted ammonium pantoate must first be converted to pantolactone, which is then racemized and which then must be converted back to ammonium pantoate so that the optical isomers in the racemic mixture can then be separated from each other.
The use of selective crystallization for separating the isomers of DL-calcium panothenate as an amide of pantoic acid is also fraught with disadvantages. After separation of the optically active isomers, sodium methoxide in an nonaqueous medium must be used to racemize the unwanted isomeric component of the mixture. If only a fraction of 1% of water is present, the calcium pantothenate is split into pantolactone and .beta.-alanine and, if 1% water is present, the yield is only 50% of the theoretical, so that this reaction step can also involve high costs unless the splitting of the calcium pantothenate during the racemization can be completely prevented. Another disadvantage of this selective crystallization method is that it is limited to calcium pantothenate, so that, when used for the preparation of D(+)-pantothenyl alcohol, optically active pantolactone is not formed and must be prepared in a separate operation.